Project Summary Invasive Salmonella disease, defined by the spread of Salmonella infection to sites distant from the gastrointestinal mucosa, is responsible for over 800,000 deaths yearly. Antimicrobial resistance is increasing against Salmonella infection, and there are no vaccines against invasive non-typhoidal Salmonella (iNTS). The proposed studies will evaluate how antigenic and phenotypic differences between different types of Salmonella, specifically S. Typhi, the two predominant iNTS strains, and typical gastroenteritis producing non-typhoidal Salmonella (NTS), impact human antigen presenting cell and T cell immune defense. The central hypothesis of this K08 application is that differences between S. Typhi, iNTS, and typical NTS lead to the initiation of different human cellular immune activation programs, which may potentially explain differences in clinical syndrome. In Aim 1 the applicant will investigate how differences between invasive and noninvasive Salmonella influence the regulation of two central cytokine pathways by human antigen presenting cells. In Aim 2, the applicant will study properties of T cells elicited in human volunteers who were previously challenged with S. Typhi, for potential cross-reactive T cell memory functions against iNTS. Aim 3 will involve analysis of differences in human macrophage activation programs between the two predominant iNTS strains and typical NTS. Understanding pathways of immune recognition, immune activation, and properties of T cell memory against invasive Salmonella may help to guide rational vaccine design against this neglected infection. This K08 application details a comprehensive, integrated 5-year training period with the goal of building from the applicant?s existing background in immunology and infectious diseases while developing new scientific skills and leadership in human cellular immunology. The applicant?s central goal for K08 training is to launch a career as an independent physician-scientist and leader in the immunology of neglected enteric infectious diseases and vaccinology. The proposal summarizes a plan for robust mentorship and scientific training, as well as foundational educational, professional, and career development activities. The K08 project will be conducted at the University of Maryland Center for Vaccine Development, an exceptional environment for research and training in translational human immunology against Salmonella, and vaccinology.